Limb-girdle muscular dystrophy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

The limb-girdle muscular dystrophies are a group of diseases that cause muscle weakness (myopathy) and wasting (atrophy). The muscles that are most affected are those closest to the center of the body (proximal muscles), specifically the muscles of the shoulders, upper arms, hips, and thighs. Signs and symptoms may appear as early as childhood and typically worsen over time.

The severity, age of onset, and specific features of limb-girdle muscle dystrophy vary among affected individuals, even among members of the same family.

In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet. Walking this way for an extended period of time can cause overgrowth (hypertrophy) of the calf muscles. Affected individuals may also have difficulty running. They may need to use their arms to push themselves up from a squatting position because of their weak thigh muscles. Over time, as myopathy and atrophy worsen, people with limb-girdle muscular dystrophy may require wheelchair assistance.

Muscle atrophy may cause changes in posture or in the appearance of the shoulders, back, and arms. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Weak back muscles may also cause an affected individual to have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some affected individuals develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows.

A weakening of the heart muscle (cardiomyopathy) occurs in some people with limb-girdle muscular dystrophy. If the weakness affects the muscles needed for breathing, affected individuals may have mild to severe breathing problems. In some cases, affected individuals need a machine to help them breathe (mechanical ventilation).

Intelligence is generally not affected in people with limb-girdle muscular dystrophy. However, developmental delays and intellectual disabilities have been reported in some affected individuals who have signs and symptoms that are more severe or that appear earlier in life.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in over 32 genes cause limb-girdle muscular dystrophy. These genes provide instructions for making proteins that are involved in muscle maintenance and repair.

Some of the proteins produced from these genes help maintain the organization and structure of muscle tissue, which allows the muscles to contract. Other proteins participate in cell signaling, cell membrane repair, or the removal of toxic waste from muscle cells.

Researchers have described several types of limb-girdle muscular dystrophy. The names for the different types include the abbreviation LGMD followed by the pattern of inheritance, a number, and the cause. Within this classification, the letter "D" is used for the forms of the disorder that have an inheritance pattern called autosomal dominant. The letter "R" is used for the forms of the disorder that have an inheritance pattern called autosomal recessive. The name also includes a number that indicates the order in which the disease was discovered, and it may include the name of the specific protein that is affected. As an example, “LGMD R1 calpain-3-related” refers to the first autosomal recessive limb-girdle muscular dystrophy to be discovered, which is caused by changes in the calpain-3 enzyme.

Variants in the CAPN3 gene are the most common cause of limb-girdle muscular dystrophy. This gene provides instructions for making an enzyme called calpain-3. The calpain-3 enzyme cuts (cleaves) damaged proteins into shorter segments so that they can be easily removed from the muscle cell. CAPN3 gene variants lead to the production of an enzyme that does not function properly. As a result, damaged proteins are not removed from muscle cells and muscle function is impaired. CAPN3 gene variants cause the LGMD R1 calpain-3-related type and the LGMD D4 calpain-3-related type of limb-girdle muscular dystrophy.

Variants in the DYSF gene are another common cause of limb-girdle muscular dystrophy. The DYSF gene provides instructions for making a protein called dysferlin, which is found in the thin membrane that surrounds muscle fibers. Dysferlin is thought to help repair this membrane when it becomes damaged due to muscle strain. DYSF gene variants cause cells to produce an altered version of the protein that cannot help with muscle repair. DYSF gene variants cause the LGMD R2 dysferlin-related type of limb-girdle muscular dystrophy.

Variants in the other genes that are associated with limb-girdle muscular dystrophy each account for a small percentage of cases.

In some people with limb-girdle muscular dystrophy, the genetic cause of the disorder is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Limb-girdle muscular dystrophy can have different inheritance patterns.

The condition is typically inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Some cases of limb-girdle muscular dystrophy are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

It is estimated that between 1 in 14,500 and 1 in 123,000 individuals have limb-girdle muscular dystrophy. It is difficult to determine the exact number of people with this condition because the features vary and may overlap with those of other muscle disorders.

Which doctor should you see?

The suggested department for discussing Limb-girdle muscular dystrophy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Limb-girdle muscular dystrophy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.